The feline and primate major histocompatibility complex (MHC) has been studied for an approach to comparative gene organization of multigene clusters in mammals. Sequence diversity and evolutionary history of mammalian MHC class II DRB genes have been studied by phylogenetic analysis of PCR amplified exon 2 region in this genes. These studies argue that (A) feline MHC DRB genes have the following characteristics: (1) 63 polymorphic DRB alleles in 37 domestic cat samples collected worldwide, (2) five phylogenetic clusters or lineages (DRB*1 to DRB*5) originated subsequent to the split of felid and canid groups, (3) some of these clusters (DRB*1, *2, *3, *5) represent at least one DRB locus, (4) recent gene duplication events in each locus, and (5) usages of different DRB loci as polymorphic loci in each feline species; (B) (1) Orangutan MHC DRB genes maintain 69 alleles, (2) Orangutan DRB genes show distinct distribution patterns compared with other hominoid MHC. Seventy percent of orangutan DRB alleles belong equally to three allelic groups, DRB1*08, DRB1*09, DRB3, and only two DRB1*03 and no DRB1*04 alleles, which are dominant groups in humans, were found in orangutan, (3) Twenty percent of orangutan alleles have a high sequence identity to the human DRB6 pseudogene, suggesting unique evolutionary histories of DRB genes in human and orangutan.